A study by researchers at Weill Cornell Medical College reveals the vital steps cancer cells undertake after they convert themselves in order to detach from a tumor and metastasize.
The study published online and in the upcoming issue of Cancer Research, highlights how cancer cells reverse the process, and switch back into classical cancer that can evolve into a new tumor.
The research was funded by a grant to the Cornell Center on the Microenvironment and Metastasis and the Neuberger Berman Foundation from the National Cancer Institute.
The team examined breast cancer and found that a single protein called versican is vital to this process. Using mice, the researchers stopped versican from functioning and found that the breast cancer cells were unable to “seed” themselves into the lungs and produce new tumors.
Dr. Vivek Mittal, senior researcher of the study, an associate professor of cell and developmental biology in cardiothoracic surgery and director of the Neuberger Berman Lung Cancer Laboratory at Weill Cornell Medical College, explained:
“Our findings both help us understand how breast cancer metastasizes to the lungs and ways to possibly prevent that deadly spread.
These are exciting insights into a poorly investigated area. There are no clinically approved drugs now that can effectively target metastatic lesions, which is why more than 90 percent of human cancer-related deaths come from spread of the disease from a primary tumor.”
Co-researcher Dr. Linda T. Vahdat, professor of medicine, chief of the Solid Tumor Service and director of the Breast Cancer Research Program at Weill Cornell, said:
“The results of this study are a critical step in deconstructing the process of metastases – which is critical to curing our patients. As a direct result of this study, we are working on ways to interrupt the process by which tumors co-opt the infrastructure in our bodies to grow and spread.”
According to Dr. Nasser Altorki, the David B. Skinner Professor of Thoracic Surgery at Weill Cornell Medical College and director of the division of thoracic surgery at NewYork-Presbyterian/Weill Cornell, this research helps to explain the mechanistic basic of cancer metastases, not only in breast cancer but potentially in other types of cancer.
“The need for a prepared and receptive soil may be required for cancer cell seeding regardless of the primary cancer’s site of origin.”
Researchers have speculated that in order for a cancer to metastasize, its “seed” must find the right “soil” in a distant organ to thrive. According to the team, this seed is produced via a method called epithelial-mesenchymal transition (EMT). During this process cancer cells detach from other cells in a primary tumor, allowing them to flow through the blood to other organs.
The researchers believe that the next stage the cells undergo is a reverse process, known as mesenchymal-epithelial transition (MET). During this process, the seeds convert back into epithelial cells, enabling them to make contact with tissues and integrate in the distant organ. Compared to EMT, researchers know very little about MET.
In the investigation, Dr. Mittal, and his team examined mouse models of spontaneous breast cancer development. The team found that a signal from primary breast tumors forces bone-marrow-derived hematopoietic cells to travel into the rodent’s lungs.
Dr. Mittal explained:
“This appears to be the soil the cancer seeds need. The next question was obvious: What is it about the soil that helps the seed?
They discovered that a subtype of these bone marrow cells expressed versican, which enabled the cancer cells to convert back into epithelial cells once they moved into the lungs. Dr. Mittal said: “The primary tumor sets up the lung microenvironment to promote metastasis. MET resulted not from properties within the cancer cell itself, but due to a unique crosstalk between the microenvironment and tumor cells in the lung.”
The researchers then injected small interfering RNAs (siRNAs) in the bone marrow that blocked versican production, which in turn prevented MET and prevented the tumor from spreading in the lung.
Using lung samples taken from breast cancer patients provided by investigators at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, the team examined human breast metastases to the lung.
Dr. Mittal explained:
“We found versican was highly expressed in those lung tumors, which matched what we found in our mice. This all made sense to us, because versican has been linked to cancer progression, although no one knew why.
This is the first study demonstrating the significance of MET in the formation of macrometastases in distant organs. Given the findings, we now have a potential strategy to stop cancer spread before it starts, or to shut it down if it has already occurred.”
The Neuberger Berman Lung Cancer Laboratory, the Robert I. Goldman Foundation and National Cancer Institute support of the Cornell Center on the Microenvironment and Metastasis, funded the study.
Study researchers include, from Weill Cornell Medical College: Dingcheng Gao, Natasha Joshi, Hyejin Choi, Seongho Ryu, Mary Hahn, Raul Catena, Patrick Wagner, Linda T. Vahdat, Jeffrey L. Port, Brendon Stiles and Nasser K. Altorki; from Johns Hopkins University: Saraswati Sukumar, Helen Sadik and Pedram Argani; and Shahin Rafii from the Howard Hughes Medical Institute and Weill Cornell Medical College.
Written by Grace Rattue